Neurodegenerative diseases such as Alzheimer's Disease (AD) mainly affect the elderly. AD is a progressive disease which results in cognitive decline and dementia. Two pathological hallmarks of AD are intracellular neurofibrillary tangles (NFTs) and extracellular senile plaques (NPs). The former accumulates inside dying cells while the latter builds up between nerve cells. Various processes have been implicated in neurodegenerative pathogenesis, including β-amyloid production, hyperphosphorylation of tau, oxidative stress, inflammation, synaptic failure and neuronal apoptosis. The actual cause of AD, however, remains elusive. One hypothesis states that neuronal loss in AD is due to the accumulation of toxic protein. β-amyloid is a cleavage product derived from amyloid precursor protein (APP), which accumulates as extracellular plaque in AD brain. Emerging studies reveal that deregulation of specific intracellular signaling pathways results in AD or Aβ-induced neuronal apoptosis. For example, activation of JNK and p38 was found to associate with the AD mice model (Savage et al. (2002) J Neurosci 22:3376-85). The glycogen synthase kinase (GSK)-3 pathway has also been shown to be involved in oxidative stress-induced neuronal cell death mechanisms (Koh et al. (2003) Brain Res Mol Brain Res 118:72-81; Takadera et al. (2004) Eur J Pharmacol. 499:239-45). Furthermore, inhibition of GSK-3 reduces Aβ-induced neurotoxicity (Koh et al. (2008) Brain Res 1188:254-62). Similarly, both Wnt and Notch signaling play roles in the pathogenesis of AD (De Strooper et al. (2001) J Cell Biol 152:F17-20; Anderton et al., (2000) Mol Med Today 6:54-9).
Currently, the clinical diagnosis of AD requires an evaluation of medical history and physical examination including neurological, neuropsychological and psychiatric assessment, as well as various biological, radiological and electrophysiological tests. Despite the battery of tests, a definitive diagnosis can only be achieved by post-mortem brain examination.
There is therefore an unmet need for a simple biochemical test that can detect neurodegeneration at an early stage and monitor progression of related diseases and disorders. Aging populations in, for example, the U.S., Europe, and China are increasingly seeking improved diagnostic and therapeutic tools for AD and other neurodegenerative disorders.
The invention relates to the association of another signal pathway to AD pathology and the identification of two novel targets involved in the molecular mechanism of AD, namely, STAT3 protein and TYK2, the upstream regulator of STAT3. STAT3 and TYK2 have major implications in the diagnosis of AD as well as in the development of therapeutic drugs against the disease. Previously, STAT3 over-expression has only been associated with inflammation and cancer.
STAT3 and its upstream regulator TYK2 both play key roles in Aβ-induced neural cytotoxicity. STAT3 phosphorylation at tyrosine 705 is elevated in the cortex and hippocampi of AD brains, which can promote apoptosis of cortical neurons, while TYK2 mediates STAT3 phosphorylation and activation. Blocking one or both of these targets can prevent Aβ-induced cell death and could potentially halt disease progression. Thus, the invention has major significance in developing drugs in the treatment of AD, as well as in the diagnosis of the disease.